Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Heralded as the stomach flu, retirement community outbreaks are pervasive and can result in 1-2% mortality rates in the elderly. Based on capsid sequences norovirus are divided into 5 genogroups. Genogroup I (GI) and II (GII) account for almost all human infections. Each genogroup is further divided into genotypes. The GII.4 genotype is the causative agent of 70-80% of all norovirus outbreaks worldwide. The norovirus major capsid protein forms an icosohedral shell, contains major antigenic determinants and interacts with histoblood group antigen (HBGA) carbohydrates, putative receptors for entry. This study investigates the molecular mechanisms governing norovirus capsid evolution, structure and HBGA recognition as a function of immune driven antigenic drift and deceptive imprinting. We identify the mechanisms by which replacement strains evolve over time, recognize new HBGA carbohydrate binding targets, and escape from highly penetrent host susceptibility alleles and protective herd immunity. While defining the relationships between mutation, antigenic variation, immunogenicity, deceptive imprinting, structure and HGBA binding, our interdisciplinary team simultaneously develops a robust GII.4 challenge model in swine and characterizes human monoclonal antibodies (mAb) to GI and GII strains, providing key reagents for advancing the field.